The field of applying active ingredients to humans and animals is, of course, wide ranging and comprises for example, the delivery and application of active ingredients for pharmaceutical and cosmetic purposes. It is specifically desirable to provide such compositions that are capable of solubilizing and stabilizing water insoluble or sparely soluble active ingredients in water.
Supramolecular Chemistry has expanded the scope of Chemistry allowing for the design and development of smart and functional materials. While traditional synthetic molecules are covalently-linked molecules or macromolecules, supramolecular complexes contain non-covalent binding on the association of two or more building blocks which are held together by intermolecular bonds, such as hydrogen bonding, dipole-dipole interactions, van der Waals forces, cation-pi interactions, pi-pi bonds, CH/pi interactions, or hydrophobic effects, and etc. showing inclusion, selectivity and other functionality.
Reversely thermo-reversible gelling systems are known in which the solution viscosity increases and decreases with an increase and decrease in temperature, respectively. Such system exhibits a solution to gel (sol-gel) transition which transforms a low viscosity solution to a higher viscosity gel form as the temperature increases, with continued increases in temperature, the gelled system then experiences a gel to solution (gel-sol) transition which transforms the gelled system back to a liquid solution. Such reversely thermo-reversible gelling systems are useful wherever it is desirable to handle a composition in a liquid state, and/or the performance of the composition in a gel form.
A known material with these properties is a reversely thermo-reversible hydrogel using water soluble block copolymers of polyethylene oxide and polypropylene oxide available commercially as Pluronic® from BASF (Ludwigshafen, Germany) and generically known as Poloxamers. Generally, about 20% w/w Pluronic® F127 aqueous solution is liquid when at or below about 25° C. or heated to temperatures exceeding 70° C., but turns into gel form and exhibits maximum viscosity in the range of 30-60° C. (see 2006 BASF Technical Bulletin entitled “Pluronic® F127 surfactant viscosity as a function of temperature & concentration”; and April 2010 “Lutrol® L and Lutrol® F-Grades”). Typically, concentrations of Pluronic® F127 polymer of at least 18-20% by weight are needed to produce a sol-gel transition temperature at about 25° C., room temperature range. To decrease the desired sol-gel transition temperature further below 25° C., a higher concentration of Poloxamer polymer has to be used which in turn increases the viscosity of solution and results in unfavorable physiological interaction during use. The freedom to use Poloxamer polymers with adjustable sol-gel transition temperatures, specifically, at temperatures below about 25° C. without employing higher concentrations of polymer, is limited.
U.S. Pat. Nos. 4,188,373, 4,478,822 and 4,474,751 disclose the use of nonionic block copolymers of polyethylene oxide and polypropylene oxide Poloxamers in aqueous pharmaceutical compositions. In these systems, the concentration of polymer is adjusted to give the desired sol-gel transition temperature. However, concentrations of the poloxamer polymer of at least 18-20% by weight are needed to produce a composition which exhibits such a transition at commercially or physiologically useful temperatures. Also, solutions containing more than 18-20% by weight of block copolymer at the desired sol-gel transition temperature are typically very viscous even in the “liquid” state. In addition, the high polymer concentrations may cause unfavorable physiological interactions with target tissue during use.
U.S. Pat. No. 5,256,396 to Piechota et al. discloses an oral composition of a water dispersible active ingredient with the use of Pluronic F127. These compositions are flowable liquids below 82° F. (27.8° C.), and gels when heated to 82° F. (27.8° C.).
U.S. Pat. No. 5,252,318 to Joshi et al. discloses reversible gelling compositions which comprise a blend of a pH-sensitive gelling polymer and a thermo-sensitive gelling polymer, such as Pluronic F 127. The sol-gel transition temperature adjustment has been achieved at relatively low Pluronic F127 polymer concentrations upon simultaneous change in temperature and pH.
U.S. Pat. No. 6,316,011 to Ron et al. discloses a reversely thermo-sensitive gelling composition comprising an end-modified block copolymer of polyethylene oxide and polypropylene oxide, the composition reversibly gelling at a temperature in the range of 22° C. to 40° C.
The references cited above are generally concerned with reversely thermo-reversible hydrogel compositions which are in a liquid state at room temperature or below, subsequently transform to a gel form when warmed to body temperature after application, and have to employ a high concentration of polymer. However, for many pharmaceutical and cosmetic products and applications, a gel form hydrogel composition is more preferred under use conditions, i.e. in the form of a gel at room temperature. In addition, the liquid state of such systems at room temperature presents a lot of challenges in regard to the solubility and/or stability of sparely soluble or insoluble active ingredients in such aqueous liquid solutions. For example, the use of salicylic acid or its derivatives for treating dandruff, acne, skin wrinkling, skin pigmentation, warts, freckles, or skin-related problems is well known in the preparation of dermatologic and cosmetic formulations. Salicylic acid and its derivatives are usually in crystalline form and are not sufficiently soluble in water or oils traditionally used in dermatological and cosmetic preparations. Typical problems that occur when using salicylic acid or its derivatives in making dermatologic and cosmetic products are that the salicylic acid and its derivatives tend to crystallize out within various compositions, which significantly reduces the bioavailability of salicylic acid and its derivatives for treating or preventing the aforementioned skin problems. Further, salicylic acid and its derivatives provide formulations that form crystals on standing and precipitate out within the solution, which is unpleasant with regard to texture and appearance from the consumer's viewpoint.
U.S. Pat. No. 8,865,143 to Lu et al. discloses reversely thermo-reversible hydrogel compositions comprising water soluble block copolymers of polyethylene oxide and polypropylene oxide and at least one associative gelling adjuvant in a temperature range of 4-45° C. The hydrogel compositions disclosed in this reference have substantial water weight, which make shipping and handling difficult and expensive, and it is not known from this reference how to overcome this disadvantage.
Accordingly, there remains a need for improved delivery compositions comprising water soluble block copolymers of polyethylene oxide and polypropylene oxide for solubilizing water insoluble or sparely soluble active ingredients, particularly reversely thermo-reversible hydrogel or solution compositions comprising such block copolymers of polyethylene oxide and polypropylene oxide, which have extended gel form under use conditions, specifically at below room temperature, and have acceptable or improved solubility and/or stability for sparely soluble or insoluble active ingredients at relatively low polymer concentration, useful for pharmaceutical and cosmetic products and applications.